Diabetes mellitus is an ever-increasing threat to human health. For example, in the United States current estimates maintain that about 16 million people suffer from diabetes mellitus.
Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of the insulin producing pancreatic β-cells, and necessitates regular administration of exogenous insulin. Without insulin, cells cannot absorb sugar (glucose), which they need to produce energy. Symptoms of Type I diabetes usually start in childhood or young adulthood. People often seek medical help because they are seriously ill from sudden symptoms of high blood sugar (hyperglycemia).
Type II diabetes, also known as non-insulin-dependent diabetes mellitus, manifests as an inability to adequately regulate blood-glucose levels. Type II diabetes may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from Type II diabetes have too little insulin or cannot use insulin effectively. Insulin resistance refers to the inability of the body tissues to respond properly to endogenous insulin. Insulin resistance develops because of multiple factors, including genetics, obesity, increasing age, and having high blood sugar over long periods of time. Type II diabetes, sometimes called mature onset, can develop at any age, but most commonly becomes apparent during adulthood. The incidence of type II diabetes in children, however, is rising.
In diabetics glucose levels build up in the blood and urine causing excessive urination, thirst, hunger, and problems with fat and protein metabolism. If left untreated, diabetes mellitus may cause life-threatening complications, including blindness, kidney failure, and heart disease.
Type II diabetes accounts for approximately 90-95% of diabetes cases, killing about 193,000 U.S. residents each year. Type II diabetes is the seventh leading cause of all deaths. In Western societies, type II diabetes currently affects 6% of the adult population with world-wide frequency expected to grow by 6% per annum. Although there are certain inheritable traits that may predispose particular individuals to developing type II diabetes, the driving force behind the current increase in incidence of the disease is the increased sedentary life-style, diet, and obesity now prevalent in developed countries. About 80% of diabetics with type ii diabetes are significantly overweight. As noted above, an increasing number of young people are developing the disease. Type II diabetes is now internationally recognized as one of the major threats to human health in the 21st century.
Type II diabetes currently is treated at several levels. A first level of therapy is through diet and/or exercise, either alone or in combination with therapeutic agents. Such agents may include insulin or pharmaceuticals that lower blood glucose levels. About 49% of individuals with Type II diabetes require oral medications, about 40% require insulin injections or a combination of insulin injections and oral medications, and 10% use diet and exercise alone.
Current therapies include: insulin secretagogues, such as sulphonylureas, which increase insulin production from pancreatic β-cells; glucose-lowering effectors, such as metformin which reduce glucose production from the liver; activators of the peroxisome proliferator-activated receptors-γ (PPAR-γ), such as the thiazolidinediones, which enhances insulin action; and α-glucosidase inhibitors which interfere with gut glucose production. There are, however, deficiencies associated with currently available treatments. For example sulphonylureas and insulin injections can be associated with hypoglycemic episodes and weight gain. Furthermore, patients often lose responsiveness to sulphonylureas over time. Metformin and α-glucosidase inhibitors often lead to gastrointestinal problems and PPAR-γ agonists tend to cause increased weight gain and edema.
There are several areas at which research is being targeted in order to bring new, more effective, therapies to the marketplace. As one example, the present inventors are exploring a reduction in excessive hepatic glucose production, enhancing the pathway by which insulin transmits its signal to the cells such that they take up glucose, enhancing glucose-stimulated insulin secretion from the pancreatic β-cells, and targeting obesity and associated problems with fat metabolism and accumulation.
Free fatty acids (FFA) play key roles in several aspects of metabolism, including the ‘priming’ of the pancreatic β-cell to potentiate the insulin response to glucose in the fasted state and as a starting point in lipogenesis. GPR40 is the first cell-surface receptor identified for fatty acids most prevalent in plasma such as palmitate, oleate, stearate, linoleate, and linolenate. GPR40 could be considered to be a ‘nutrient sensing’ receptor, playing several tissue-dependent roles which may inter-play to effect overall glucose disposal and/or fat metabolism. For example, and herein incorporated by reference, Itoh et al. (Nature, 23 Feb. 2003, doi:10.1038/nature01478) describe that long-chain FFAs amplify glucose-stimulated insulin secretion from the pancreatic β cells through activation of GPR40.
On this basis, agonists to GPR40 may be of therapeutic value for diabetes and associated conditions, particularly type II diabetes, obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, atherosclerosis, neurodegenerative diseases (for example Alzheimer's disease), and other indications such as stroke.